Autonomic: Angiotensin-(1-7) Interactions in Hypertension

自主神经：高血压中血管紧张素 (1-7) 的相互作用

• 批准号: 8821988
• 负责人: Amy Christine Arnold
• 金额: $ 12.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821988
• 关键词: Acute; Address; Angiotensin II; Angiotensin II Receptor; Animal Model; Animals; Area; Autonomic nervous system; Autonomic nervous system disorders; Baroreflex; Biometry; Blood Pressure; Buffers; Cardiovascular system; Cause of Death; Cessation of life; Characteristics; Chronic; Clinical; Clinical Research; Complement; Data; Development; Disease; Educational process of instructing; Environment; Etiology; Euglycemic Clamping; Experimental Animal Model; Experimental Models; Extramural Activities; Failure; Feedback; Foundations; Fructose; Functional disorder; Generations; Glucose Clamp; Goals; Gold; Hepatic; Hormones; Human; Hypertension; Hypotension; Impairment; Infusion procedures; Insulin; Insulin Resistance; Intravenous; Journals; Laboratory Animal Production and Facilities; Link; Maintenance; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metabolism; Methods; Modeling; Molecular; Neurosciences; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Pharmacology; Phase; Physicians; Physiological; Physiology; Plasma; Play; Population; Public Health; Rattus; Regulation; Renin-Angiotensin System; Research; Research Personnel; Residual state; Resources; Review Committee; Rodent; Role; Scientist; Services; Site; Stroke; Sympathetic Nervous System; Sympatholytics; Testing; Training; Universities; Vasodilation; angiotensin I (1-7); autonomic reflex; base; blood pressure reduction; cardiovascular disorder risk; career; career development; experience; feeding; heart disease risk; improved; in vivo; indexing; innovation; insulin sensitivity; neuromechanism; novel; patient population; programs; receptor; relating to nervous system; restraint; skills; targeted treatment; translational approach; treatment strategy

DESCRIPTION (provided by applicant): Project Summary Hypertension is a major public health problem associated with an increased risk for heart disease and stroke, leading causes of death worldwide. The majority of hypertensive subjects are now obese and many suffer from insulin resistance, but the molecular mechanisms linking cardiovascular and metabolic derangements in this disease are not fully understood. Increasing evidence suggests that the renin-angiotensin system (RAS), in particular overactivity of angiotensin (Ang) II, plays a pathogenic role in both hypertension and insulin resistance in part through modulation of the sympathetic nervous system. More recently, the vasodilatory peptide Ang-(1-7), which opposes Ang II actions, has been implicated in the pathogenesis of hypertension. While Ang-(1-7) lowers blood pressure and improve insulin action in rodents, the precise mechanisms involved in these effects are unclear. In addition, there are limited and contradictory studies in humans, and we propose that this is due to restraint of Ang-(1-7) cardiovascular actions by autonomic buffering mechanisms. We also propose that Ang-(1-7) improves cardiovascular and metabolic function by inhibiting the sympathetic nervous system. Indeed, our preliminary data suggests that plasma Ang-(1-7) levels are reduced in clinical populations with sympathetic activation. Furthermore, this Ang-(1-7) deficiency appears to interact with the sympathetic nervous system to contribute to hypertension and insulin resistance. Based on these findings, we will test the overall hypothesis that Ang-(1-7) lowers blood pressure and improves insulin sensitivity by opposing the sympathetic nervous system. We will use an innovative translational approach to test this hypothesis that combines integrative physiologic and pharmacologic methods in animal and human experimental models. In Aim 1, we will take advantage of the unique characteristics of central and peripheral autonomic failure patients to determine the contribution of sympatholytic and peripheral vasodilatory mechanisms, respectively, to Ang-(1-7) effects in the absence of baroreflex buffering. In Aim 2, we will examine Ang-(1-7) effects on peripheral and hepatic insulin sensitivity in fructose-fed rats, an established animal model of cardio-metabolic syndrome, and whether these effects involve sympathetic inhibition. Finally, in the independent phase, the PI will examine the importance of endogenous Ang-(1-7): sympathetic interactions to cardiovascular and metabolic function in fructose-fed rats. These collective studies will accomplish the PIs short-term research objective to examine interactions between the sympathetic nervous system and Ang-(1-7) for cardiovascular and metabolic regulation. The findings from these studies will improve our understanding of mechanistic pathways of the RAS, and have the potential to advance current concepts in the field of hypertension to improve targeted treatment approaches and outcomes in this disease. These studies logically build upon the PI's translational background in cardiovascular autonomic regulation, and will provide strong training and a research framework to establish an independent and novel area of research. The PI will acquire new expertise and skills in cutting edge methods to assess insulin action in rodents in the mentored phase of this application, to complement her integrative animal and clinical cardiovascular training and to provide the foundation to be an elite investigator with the capabilities to comprehensively investigate cardio-metabolic function. The clinical studies will be performed under the mentorship of Dr. Italo Biaggioni at Vanderbilt University, a world renowned physician scientist with expertise in neural-metabolic interactions, and in autonomic disorders including primary autonomic failure. The PI will receive training in hyperinsulinemic-euglycemic clamps under the co-mentor Dr. David Wasserman, an expert in metabolism with over 20 years of experience in these methods. The PI has also established an outstanding mentoring team with a proven track record of mentorship and scientific expertise in the RAS, experimental and clinical hypertension, autonomic neuroscience, and biostatistics. Thus, these studies will be conducted in the optimal scientific environment with input from highly experienced mentors, access to unique patient populations, state-of-the-art clinical research and animal facilities, and a wealth of institutional resources for career development. Finally, the PI will participate in extramural activities to enhance her progression into an independent investigator including continued service on national physiology, pharmacology and autonomic committees, reviewing for journals and participating in teaching and mentorship opportunities. Overall, this proposal will advance the PIs long-term research and career goals, to establish a translational independent research program focused on the neural mechanisms of hypertension.

描述(由申请者提供)：高血压是一个主要的公共卫生问题，与心脏病和中风风险的增加有关，是全球主要的死亡原因。现在，大多数高血压患者都是肥胖的，许多人患有胰岛素抵抗，但这种疾病中心血管和代谢紊乱的分子机制还不完全清楚。越来越多的证据表明，肾素-血管紧张素系统(RAS)，特别是血管紧张素(Ang)II的过度激活，在高血压和胰岛素抵抗中起着致病作用，部分是通过调节交感神经系统来实现的。最近，血管扩张多肽Ang-(1-7)被认为与高血压的发病机制有关，Ang-(1-7)是一种拮抗Ang II作用的物质。虽然Ang-(1-7)能降低血压并改善啮齿动物的胰岛素作用，但这些作用的确切机制尚不清楚。此外，在人类中也有有限和相互矛盾的研究，我们认为这是由于自主神经缓冲机制抑制了Ang-(1-7)心血管活动。我们还提出Ang-(1-7)通过抑制交感神经系统来改善心血管和代谢功能。事实上，我们的初步数据表明，在交感神经激活的临床人群中，血浆Ang-(1-7)水平降低。此外，这种Ang-(1-7)缺乏似乎与交感神经系统相互作用，导致高血压和胰岛素抵抗。基于这些发现，我们将检验Ang-(1-7)通过对抗交感神经系统来降低血压和改善胰岛素敏感性的总体假设。我们将使用一种创新的翻译方法来验证这一假设，该方法结合了生理学和药理学的综合方法，在动物和人类实验模型中。在目标1中，我们将利用中枢和外周自主神经衰竭患者的独特特征来确定在没有压力感受性反射缓冲的情况下，交感神经溶解和外周血管扩张机制分别对Ang-(1-7)效应的贡献。在目标2中，我们将检测Ang-(1-7)对果糖喂养大鼠的外周和肝脏胰岛素敏感性的影响，以及这些影响是否涉及交感神经抑制。最后，在独立阶段，PI将检查内源性Ang-(1-7)：交感神经相互作用对果糖喂养大鼠心血管和代谢功能的重要性。这些集体研究将完成PIS的短期研究目标，以检查交感神经系统和Ang-(1-7)之间的相互作用，以进行心血管和代谢调节。这些研究的发现将提高我们对RAS机制的理解，并有可能推动高血压领域的现有概念，以改进这种疾病的靶向治疗方法和结果。这些研究在逻辑上建立在PI在心血管自主神经调节方面的翻译背景之上，并将提供强有力的培训和研究框架，以建立一个独立和新颖的研究领域。在这项应用的指导阶段，PI将在尖端方法方面获得新的专业知识和技能，以评估啮齿动物的胰岛素作用，以补充她的动物和临床心血管综合培训，并为成为一名精英研究员奠定基础。 全面研究心脏代谢功能的能力。这些临床研究将在范德比尔特大学的伊塔洛·比亚乔尼博士的指导下进行，比亚乔尼博士是世界著名的内科科学家，在神经-代谢相互作用以及包括原发性自主神经衰竭在内的自主神经障碍方面拥有专业知识。PI将在共同导师大卫·沃瑟曼博士的指导下接受高胰岛素-正常血糖夹的培训，大卫·沃瑟曼博士是一位新陈代谢专家，在这些方法方面有20多年的经验。PI还建立了一支出色的指导团队，在RAS、实验和临床高血压、自主神经科学和生物统计学方面拥有良好的指导记录和科学专业知识。因此，这些研究将在最佳的科学环境中进行，经验丰富的导师将提供意见，获得独特的患者群体，最先进的临床研究和动物设施，以及丰富的职业发展机构资源。最后， PI将参加校外活动，以促进她成为一名独立的调查员，包括继续在国家生理学、药理学和自主委员会服务，审查期刊，并参与教学和辅导机会。总体而言，这项建议将推进PIs的长期研究和职业目标，建立一个专注于高血压神经机制的翻译独立研究计划。